DE3026365A1 - NEW TETRAHYDROPYRIDINE-4-YL-INDOLDERIVATES AND THEIR SALTS, THEIR PRODUCTION, THEIR USE AS A MEDICINAL PRODUCT AND THE COMPOSITIONS THEREOF - Google Patents

Description

- 4 ROUSSEL-UCLAF, Paris / France

New Tetrahydropyridin ~ 4-yl-indole Derivatives --- and their salts, their production,

their use as medicaments and the compositions containing them

description

The invention relates to new tetrahydropyridin-4-yl-indole derivatives as well as their salts, their production, their use as medicaments and the compositions containing them.

The invention relates to new tetrahydropyridin-4-yl-indole derivatives and their addition salts with mineral or organic acids, which are characterized in that they are of the general type Formula I:

Γ — Η

(D

correspond to where
R.

a methylthio, amino or trifluoromethyl radical means and

is a hydrogen atom or an alkyl radical with 1 to Represent 2 carbon atoms.

In general formula I and in the following, the term alkyl radical with 1 to 3 carbon atoms denotes e.g.

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a methyl, ethyl or propyl radical.

, The substituent R can be in all positions of the Indoles are, however, preferably in the 5- or 6-position, in particular in the 5-position.

The addition salts with mineral or organic acids can be, for example, the salts formed with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, propionic acid, benzoic acid, Maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, oxalic acid, glyoxylic acid, aspartic acid, alkanesulf onic acids, such as methane or ethanesulphonic acid, arylsulphonic acids, such as benzene or p-toluenesulfonic acid, and aryl carboxylic acids.

Among the products according to the invention one can in particular name the derivatives corresponding to the above formula I and their addition salts with mineral or organic acids, which are characterized in that in the formula I R- and Rp represent a hydrogen atom.

Among these, one can especially mention 5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -lH-indole as well as its addition salts with mineral or organic acids.

The invention also relates to a process for the preparation of the derivatives defined by the above formula I as well as of their salts, which is characterized in that a compound of the formula II:

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wherein R, R _-1 and Rp have the meaning given, with; 4-piperidone hydrochloride is reacted in an alkaline medium or in an acidic medium to obtain a derivative of the formula I which is isolated and, if desired, converted into a salt. ■

Under the preferred conditions for practicing the invention is the manufacturing process described above characterized in that the implementation of the product of

ι Formula II with the 4-piperidone hydrochloride in 2n-Methc.nolischer;

Potassium hydroxide solution is carried out, but also j Can use caustic soda or an alkali alcoholate.

The reaction is advantageously carried out under reflux of the reaction 'mixture. ;

If the 1- or 2-position of the indole is substituted, the 1

Implementation of the product of the formula II with the 4-piperidone hydro- j

Chloride preferably carried out in an acidic medium, j preferably acetic acid is used.

The derivatives of the formula I have a basic character. One can advantageously use the addition salts of the derivatives of the formula I produce by adding a mineral or organic acid in essentially stoichiometric proportions the derivative of formula I converts. The salts can be prepared without isolating the corresponding bases.

The derivatives according to the invention have very interesting pharmacological properties. They are above all with remarkable properties, which are to antidepressant and anti-Parkinson properties ^one can see is, well equipped simultaneously with anti-emetic properties.

These properties are discussed below in the experimental section illustrated.

These properties justify the use of the tetrahydropyridin-4-yl-indole derivatives of the formula I and their

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pharmaceutically acceptable salts as medicaments.

The invention thus also relates to the use of the tetrahydropyridin-4-yl-indole derivatives of formula I and v, n their addition salts with pharmaceutically acceptable acids as Drug.

Among the medicaments according to the invention, preference is given to the medicaments which are characterized in that they are derived from the new tetrahydropyridin-4-ylindole derivatives of the formula I, in which R ₁ and Rp represent a hydrogen atom and R has the meaning given, as well as their addition salts with pharmaceutically acceptable acids.

Among the latter, 5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -lH-indole is mainly used as well as its addition salts with pharmaceutically acceptable acids.

The medicaments according to the invention are used, for example, in treatment mental disorders, behavior disorders, character disorders, in the treatment of akinetic and dyskinetic ones Conditions as well as use in the treatment of vomiting and nausea of all origins.

The usual dose, which can be varied according to the product used, the patient and the disease in question, can e.g. 5 to 500 mg per day when administered orally to the adult in the case of the derivative of Example 1.

The invention finally relates to pharmaceutical compositions, the at least one of the aforementioned derivatives or one of their addition salts with pharmaceutically acceptable ones Contains acids as an active ingredient.

The derivatives corresponding to formula I and their addition salts with pharmaceutically acceptable drugs can be used as medicaments Acids are introduced into pharmaceutical compositions,

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-B-

intended for intestinal administration or parenteral administration.

These pharmaceutical compositions can, for example, solid or liquid and are in the pharmaceutical forms commonly used in human medicine v / ground, such as simple or sugar-coated tablets, gelatin capsules, granules, Sup positorien and injectable preparations. They are manufactured using the usual iXI methods. The active ingredient (s) can usually be incorporated into excipients such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting agents. , Dispersants or emulsifiers and preservatives.

The products of the formula II in which R is a methylthio radical, can be made by adding an indole of formula III:

■ (in)

with C'ipromercaptat implemented.

An example of such manufacture is given below stated in the experimental part.

The following examples illustrate the invention.

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example 1

S-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -1 H -indole hydrochloride

Step A: 5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -IH-indole

The mixture is stirred in an inert atmosphere, 11.75 g of 5-methylthio-1H-

3 mdol with 22.1 g of 4-piperidone hydrochloride hydrate and 108 cm 2N methanolic potassium hydroxide solution, bring the suspension obtained to reflux for 16 hours, cool, pour the mixture into 1 liter Ice water, stir for 15 minutes, filtered, washed with water, dried, crystallized from a mixture of ethyl acetate and methanol (10/3) to obtain 14.8 g of yellow crystals with a melting point of 210 ° C.

Level B; Manufacture of the hydrochloride

3 g of the base obtained in the previous stage are suspended in 300 cm of ethyl acetate and formed at 0 to 5 ° C. by addition of ethyl acetate containing hydrogen chloride, the hydrochloride, filtered, Washed with ethyl acetate, dried in vacuo and obtained 3 g of yellow crystals with a melting point of 240 ° C.

Analysis: C ₁₄ H ₁₇ N ₂ SCl = 280.82

Calculated: C "59.88 H 6.10 M 9.98 S a1.42 Cl 12.62% Found: 59.9, 6.1 9.7 11.3 12.6%

Production of 5-methylthio-1H-indole

With stirring, 22.7 g of 5-bromine-1H-

3 3

indole with 230 cm quinoline, 34 cm anhydrous pyrolene and 16 g of cupromethyl mercaptate, prepared according to Engelhardt [j.Med.Chem. 11 ^, 329 (1968)], to reflux, cools, falls the mixture in 1 l of 2N hydrochloric acid is added, 1 l of ethyl acetate is added, filtered, decanted, washed with 2N hydrochloric acid and with salt water, dry, drive off the solvents under reduced pressure at 40 C and recover 17.8 g of a chestnut oil. The oil obtained is purified by chromatography on silica using a

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Mixture of cyclohexane and benzene (l / l) elutes and wins 11.75 g of orange oil. ".. -

Analysis: CgHgNS = 163.243

Calculated: 3 19.64 %
Found: 19.4 %

Example 2

Tablets were made with the following formulation:

5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -lH-indole hydrochloride - 10 mg

Excipient q. see for a tablet with a final weight of 100 mg (components of the excipient: lactose, starch, talc, magnesium tearat)

Phariracological examination

1) Porsolt test

The experiments are carried out on groups of 5 male mice with a gain of approx. 20 g. The one to be examined Compound is administered intraperitoneally.

The antidepressant activity is determined according to the Porsolt test, described in Arch.Int.Pharmacodyn.Ther-p. 229 , 327 (1977).

The mice are immersed in a pecipienx filled with water which they cannot escape, which induces immobility in them. Decrease the antidepressants the duration of this immobility.

The compound of Example 1 greatly reduced the immobility of the mice at a dose of 4 mg / kg.

2) Antagonism test against catalepsy induced by prochlorpemazine

The experiments are carried out on groups of 5 male rats

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· ■ X J. ™

carried out with a weight of approx. 100 g.

The compound to be tested is injected intraperitoneally at the same time with an intraperitoneal dose of 15 mg / kg? rochlorpemazine administered.

Catalepsy is diagnosed every hour for 7 hours following the homolateral cross-paw test (Boissier, Simon, Therapy, 1963, 18_, 1257-1277) with the following Evaluation determines:

The animal refuses to cross the front paws with the homolateral hind paws (0), it takes the desired cross only on one side (0.5), it assumes the intersection on both sides (1).

The compound of Example 1 acts as a result of prochlorpemazine induced catalepsy at a dose of 0.2 mg / kg.

3) anti-emetic activity

Antagonism to apomorphine induced vomiting has been studied in the dog (Chen and Ensor, J. Pharmac. exp.Therap. 1959, 9_3, 245-250).

The number of by subcutaneous injection of 0.1 mg / kg apomorphine hydrochloride induced vomiting is always Animal determined 8 days before the experiment.

The 7th compound to be investigated, brought into an aqueous solution is administered subcutaneously in variable doses 1/2 hour before the apomorphine hydrochloride.

The compound of Example 1 reduces apomorphine induced vomiting at a dose of 1.5 mg / kg by about 50 %.

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4) Investigation of the general toxicity

The acute toxicity is determined on groups of 10 mice weighing about 20 g, which are increased intraperitoneally Doses of the compound to be tested administered.

Mortality is 48 hours after compound administration determined.

The approximate LD _{50 of} the compound of Example 1 is 150 mg / kg,

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Claims (9)

Dr. F. Zumstein Sr. Dr E. Assmann - Or. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Kling ^ eiüan - Dr. F. Zumstein jun. PATENTAN * ALTE BOOO Munich 2 ■ BrBuhausstraQe 4 · Telephone collection no. 2253 41 Telegrams Zumpat Telex 529979 Cas 1885a / F / D claims. 1. New tetrahydropyridin-4-yl-indole derivatives, thereby characterized in that they have the general formula I: N-H (D correspond to where R denotes a methylthio, amino or trifluoromethyl radical and R _-1 and Rp represent a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms. se like their addition salts; with mineral or organic Acids. 2. Tetrahydropyridin-4-yl-indole derivatives of the formula I according to £ claim 1, characterized in that R ^ and R "denote a hydrogen atom, as well as their addition salts with mineral or organic acids, 3. 5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -1H-indole as well as its addition salts with mineral or organic acids. 030065/0908 4. Process for the preparation of tetrahydropy ;. idin-4-yl derivatives of the formula I according to claim 1 and of their addition salts with mineral or organic acids, d -a through marked that one is a product of formula II; wherein R, R and R ₂ have the meaning indicated, is reacted with 4-piperidone hydrochloride in an alkaline medium or in an acid medium, a derivative to obtain the formula "I, which is isolated and, if desired, converted into a salt.. - 5. The method according to claim 4, characterized in that the reaction of the product of formula II with the 4-piperidone hydrochloride is carried out in 2N methanolic potassium hydroxide solution, 6. Medicinal product, characterized in that it consists of the tetrahydropyridin-4-yl-indole derivatives of the formula I according to claim 1 or from their addition salts with pharme.zeutisch compatible acids exist. 7. Medicament according to claim 6, characterized in that it consists of tetrahydropyridin-4-yl-indole derivatives according to claim 2 as well as their addition salts with pharmaceutically acceptable acids. 8. Medicament according to claim 6, characterized in that it consists of 5-methylthio-3- (1,2,3,6-tetrahydropyridin-4-yl) -lH-indole as well as from its addition salts with pharmaceutical compatible acids exist. 9. Pharmaceutical compositions, characterized in that 030065/0306 that they as active ingredient at least one of the drugs according to any one of claims 6, 7 or 8 included. 030065/0906